Muscle-invasive Bladder Cancer
Conditions
Brief summary
This is a global Phase III, randomized, placebo-controlled, double-blind study designed to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with placebo in participants with MIBC who are circulating tumour deoxyribonucleic acid (ctDNA) positive and are at high risk for recurrence following cystectomy.
Interventions
DRUGAtezolizumab
ctDNA positive participants will receive 1680 mg IV, every 4 weeks (Q4W) on Day 1 of each 28-day cycle.
OTHERPlacebo
ctDNA positive participants will receive placebo IV, Q4W on Day 1 of each 28-day cycle
DEVICESignatera
Signatera will be used to evaluate whether ctDNA is detected during serial monitoring of peripheral blood samples for participants enrolled in surveillance. Participants with a ctDNA positive result will be screened for inclusion in the treatment phase. Participants who remain ctDNA negative at 12 months from the date of cystectomy will not be randomized to treatment and will enter surveillance follow-up.
Sponsors
Hoffmann-La Roche
Natera, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Following the primary analysis, the Sponsor has been unblinded, and the investigators can now be unblinded upon request to guide treatment decisions.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria for the Surveillance Phase: * Histologically confirmed MIUC (also termed transitional cell carcinoma \[TCC\]) of the bladder * Tumor, nodes, and metastases (TNM) classification (based on American Joint Committee on Cancer \[AJCC\] Cancer Staging Manual, 8th Edition; Amin et al. 2016) at pathological examination of surgical resection specimen as follows: For participants treated with prior neoadjuvant chemotherapy (NAC): tumor stage of ypT2-4a or ypN+ and M0. For participants who have not received prior NAC: tumor stage of pT2-4a or pN+ and M0 * Surgical resection of MIUC of the bladder * Participants who have not received prior platinum-based NAC must be ineligible for cisplatin-based adjuvant chemotherapy, have refused it, or will not receive it based on physician's decision * ctDNA assay developed based on tumor tissue specimen and matched normal DNA from blood * Tumor programmed death ligand (PD-L1) expression per immunohistochemistry (IHC) that is evaluable by central testing of a representative tumor tissue specimen * Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan of the pelvis, abdomen, and chest no more than 4 weeks prior to enrollment * Full recovery from cystectomy and enrollment within 24 weeks following cystectomy. Minimum of 6 weeks must have elapsed from surgery Additional Inclusion Criteria for the Treatment Phase: * Blood for plasma ctDNA sample evaluated to be ctDNA positive, defined as the presence of two or more mutations out of the 16 mutations identified based on participant' whole exome sequencing (WES) evaluable (ctDNA assay designability) report * Absence of residual disease and absence of metastasis, as confirmed by a negative baseline CT or MRI scan of the pelvis, abdomen, and chest no more than 28 days prior to randomization, as assessed by the investigator and Independent Review Facility * Eastern cooperative oncology group (ECOG) performance status of ≤ 2 * Life expectancy ≥12 weeks * Adequate hematologic and end-organ function * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs
Exclusion criteria
General Medical
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed (INV) - Disease-free Survival (DFS) | Randomization up to first occurrence of DFS event (up to approximately 49 months) | INV-DFS, defined as the time from randomization to the first occurrence of a DFS event, defined as any of the following: * Local (pelvic) recurrence of urothelial carcinoma (UC) (including soft tissue and regional lymph nodes); * Urinary tract recurrence of UC (including all pathological stages and grades); * Distant metastasis of UC; * Death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | Randomization up to death from any cause (up to approximately 6 years) | OS, defined as the time from randomization to death from any cause. |
| Independent Review Facility (IRF)-assessed DFS | Randomization up to first occurrence of DFS event (up to approximately 49 months) | — |
| INV Disease-specific Survival (DSS) | Randomization to death from UC (up to approximately 6 years) | INV-DSS, defined as the time from randomization to death from UC per investigator assessment of cause of death. |
| INV Distant Metastasis-free Survival (DMFS) | Randomization to diagnosis of distant metastases or death from any cause (up to approximately 49 months) | INV-DMFS, defined as the time from randomization to the diagnosis of distant (i.e., non-locoregional) metastases or death from any cause. |
| Time to Confirmed Deterioration of Function and Health-related Quality of Life (HRQoL) | Randomization to participant's first score decrease of ≥ 10 points from baseline on EORTC QLQ-C30 physical function scale, role function scale, and the GHS/QoL Scale (up to approximately 49 months) | Time to confirmed deterioration of function and HRQoL, defined as the time from randomization to the date of a participant's first score decrease of ≥ 10 points from baseline on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) physical function scale, role function scale, and the global health status (GHS)/QoL scale (separately), held for at least two consecutive time points or followed by death. |
| ctDNA Clearance | Baseline, Cycle 3 Day 1 or Cycle 5 Day 1 (each cycle is 28 days) | ctDNA clearance, defined as the proportion of participants who are ctDNA positive at baseline and ctDNA negative at Cycle 3, Day 1 or Cycle 5, Day 1. |
| Percentage of Participants With Adverse Events (AEs) | Baseline up to approximately 6 years | — |
| Serum Concentration of Atezolizumab | At pre-defined intervals from first administration of study drug (up to approximately 49 months) | — |
| Incidence of Anti-Drug Antibodies (ADAs) to Atezolizumab | Baseline up to approximately 49 months | Incidence of ADAs to atezolizumab after initiation of study treatment (postbaseline incidence). |
| Prevalence of ADAs to Atezolizumab | Baseline | Prevalence of ADAs to atezolizumab at baseline. |
Countries
Argentina, Belgium, Brazil, China, Colombia, Czechia, France, Germany, Greece, Hong Kong, Ireland, Israel, Italy, Japan, Mexico, Poland, Russia, Singapore, South Korea, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed